Month: June 2017

Cancer tumours manipulate a natural cell process to promote their survival suggesting that controlling this mechanism could stop progress of the disease, according to new research led by the University of Oxford.

Non-sense mediated decay (NMD) is a natural physiological process that provides cells with the ability to detect DNA errors called nonsense mutations. It also enables these cells to eliminate the mutated message (decay) that comes from these faulty genes, before they can be translated into proteins that can cause disease formation. NMD is known among the medical community for the role it plays in the development of genetic diseases such as Cystic Fibrosis and some hereditary forms of cancers. But not all nonsense mutations can elicit NMD, so until now, it’s wider impact on cancer was largely unknown.

Biomedical researchers and computer scientists from the University of Oxford Medical Sciences Division and the University of Birmingham developed a computer algorithm to mine DNA sequences from cancer to accurately predict whether or not an NMD would eliminate genes that had nonsense mutations. The work originally focused on ovarian cancers, and found that about a fifth of these cancers use NMD, to become stronger. This is because NMD ensures that the message from a gene called TP53, which ordinarily protects cells from developing cancer is almost completely eliminated. In the absence of NMD, a mutated TP53 might still retain some activity but NMD ensures that this is not the case.

Based on this research, the team predicts that because cancers essentially feed on NMD, they become dependent on it in some cases. If scientists were therefore able to inhibit or control the process, it is possible that they could also control cancer and prevent the progression of the disease.

Dr Ahmed Ahmed, Co-author and Professor of Gynaecology Oncology at the Nuffield Department of Obstetrics & Gynaecology and the head of the Ovarian Cancer Cell Laboratory, at the Weatherall Institute of Molecular Medicine at the University of Oxford, said: “Our first observations of evidence of the role of NMD in ovarian cancer were tantalizing. We found that NMD precisely explained why there was almost no expression of TP53 in certain ovarian cancers. We went on to test the role of NMD in other cancer types and the evidence of the role of NMD was compelling. This opens the door for exciting possibilities for customised treatments including individualized immunotherapies for patients in the future.”

Following the ovarian cancer analysis, the team expanded the study to include other cancer types. They analysed about a million different cell mutations in more than 7,000 tumours from the Cancer Genome Atlas covering 24 types of cancer. The team was able to map how each cancer type used NMD revealing the remarkable extent to which NMD helps cancer to survive.

Katherine Taylor, CEO of Ovarian Cancer Action, who part-funded the research, said: “This is very exciting news. Professor Ahmed and his team have identified how cancer cells rely on a process called NMD for their survival. This discovery could help clinicians identify and inhibit the process, giving them much better control of a person’s cancer.

“Ovarian cancer is a very complicated disease and survival rates are low, with only 46% of women living beyond five years after diagnosis. So understanding how we can prevent the disease from thriving is imperative if we are to improve the outcome for more women.

“It’s fantastic to see how our funding is helping make real progress and we couldn’t do this without the generosity of our supporters. We look forward to seeing where Professor Ahmed takes his research next.”
Moving forward the team will focus on testing their theory and understanding to what degree stopping the NMD process allows them to control tumours.

Co-author, Dr Christopher Yau, a computational scientist at the Institute of Cancer and Genomic Sciences, University of Birmingham said: “As a result of these findings, we now plan to apply the same computer algorithm to determine if NMD affects cancer patients in The 100,000 Genomes Project. These investigations may pave the way to new treatment possibilities for NHS patients in the future.”

With 20,000 diagnoses each year, ovarian cancer is the ninth most common cancer and fifth leading cause of cancer death among women in the United States. So many women die from ovarian cancer because it often goes undetected until it has spread within the pelvis and abdomen, by which point it is difficult to treat and usually fatal.

A team of researchers from the University of California, Riverside and the University of Notre Dame are studying the molecular mechanisms by which ovarian cancer spreads—or metastasizes—to uncover new therapeutic opportunities.
In their latest paper, published in the journal Oncogene, they used live imaging and electron microscopy to study the cellular activities associated with successful metastasis, including the expression of a group of proteins called cadherins, which help cells bind together. Since these proteins enable cancer cells to anchor to new sites in the body, it may be possible to disrupt metastasis by blocking cadherin-mediated binding.

The research was led by Mark Alber, a distinguished professor of applied mathematics at UC Riverside, and M. Sharon Stack, a Kleiderer-Pezold professor of biochemistry and director of Notre Dame Harper Cancer Research Institute.

As primary ovarian tumors metastasize, they shed both single cells and clusters of cells, called multicellular aggregates (MCAs), into the pelvis and abdomen. To study exactly how metastasis occurs, the researchers quantified the interactions between epithelial ovarian cancer (EOC) cells and three-dimensional models of the abdomen wall. They showed when EOC cells acquired N-cadherin (Ncad), an event that occurs in human EOC tumors, they could penetrate and attach to the abdomen wall. Furthermore, MCAs dispersed prior to invasion as a large cohort of cells, showing that cell to cell junctional integrity (i.e. attachment at the single cell level) was needed for successful metastasis.

Alber said unlike results observed in other cancers, ovarian cancer cells do not appear to exhibit a ‘leader-follower’ type of collective cell invasion.

“Interestingly, co-culture of Ncad-expressing cells with cells expressing E-cadherin (Ecad) did not promote invasion of the Ecad-expressing cells, demonstrating that Ncad-expressing cells do not simply lead the way for other cell populations to follow,” Stack said.

The findings emphasize the importance of Ncad in ovarian cancer metastasis and provide the rationale to support pre-clinical studies using Ncad-blocking molecules as a therapeutic strategy to suppress EOC metastatic anchoring.

The group is using these results to develop computational models of cancer cell invasion. Future studies will also use patient samples, which will be provided by collaborators from the City of Hope, in Duarte, Calif. for combined modeling and experimental approaches to obtain novel insights into the cellular mechanisms of ovarian cancer metastasis.

Doctors often don’t hear about the serious side effects of chemotherapy because patients are reluctant to complain or don’t have enough time to talk about such problems during jam-packed office visits, experts say.

But a new study points to a potential solution: using simple technology to encourage “real time” reporting of symptoms. Its findings show that patients with advanced cancer who reported side effects frequently via an online tool lived a median of five months longer than those who waited to mention problems during office visits.

Lead study author Ethan Basch, an oncologist at Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill, acknowledges that a five-month improvement might sound modest. But, he notes, it is a greater benefit than what’s provided by many targeted drugs for metastatic cancer.

Results of Basch’s randomized, controlled trial were published Sunday morning in JAMA and will be presented at the plenary session of the American Society of Clinical Oncology annual meeting in Chicago. Onlyfour studies, thought to have the greatest potential to affect patient care, are being highlighted at that session.

The trial involved 766 patients who were receiving outpatient chemotherapy at Memorial Sloan Kettering Cancer Center in New York, where Basch practiced before moving to Lineberger. The patients had a variety of cancer types, including prostate, breast and lung.

One group was directed to report the common side effects of chemo — including nausea, pain, fatigue and difficulty in breathing — at least once a week using an electronic tablet or other kind of computer. Nurses got email alerts when participants reported worsening symptoms.

The other group reported side effects in the usual way — during monthly meetings with oncologists and by telephone if concerns came up between visits.

The study found that patients who reported their side effects more frequently via the Web-based tool got quick attention from nurses, who frequently adjusted medications for nausea, constipation and pain. As a result, Basch said, those patients had fewer emergency room visits, were able to tolerate chemo longer and were more active — all factors that contributed to their living five months longer than the patients who were not in the real-time reporting group.

Scott Ramsey, director of the Hutchinson Institute for Cancer Outcomes Research at the Fred Hutchinson Cancer Research Center in Seattle, said Basch’s approach represents a “promising, low-cost way to reduce suffering and save millions of dollars in preventable emergency-department visits.”

Ramsey, who was not involved in the study, said that most oncology practices rely on patients to contact their offices when they run into trouble during chemotherapy. “But unfortunately, most patients don’t know when to call for help and often wait until it’s too late,” he said. In Washington state, more than 50 percent of chemotherapy patients end up at the E.R. or in the hospital within six months of starting treatment, according to Ramsey.

Basch is now leading a national trial involving 1,000 patients being treated in community oncology practices around the country. It uses a tool that works on cellphones.

Challenges confront the implementation of real-time symptom reporting, including the way that electronic medical records are set up and a lack of reimbursement for physicians, Basch said. But those obstacles are surmountable, he added.

“We have limited time to see a lot of people as oncologists,” he said. “But we can harness technology to improve the quality of how we practice and to bring us closer to our patients.”

Immunotherapy combinations with PARP inhibitors or checkpoint inhibitors may represent the future of treatment for patients with ovarian cancer, said Samir N. Khleif, MD, during the 2017 ASCO Annual Meeting.

Alternatives to chemotherapy are needed for the treatment of ovarian cancer because despite an 80% response to chemotherapy, recurrence is universal with few options available following recurrence. Ovarian cancer is an immune-dependent cancer; ovarian cancers with T-cell infiltration within the tumor microenvironment are associated with superior progression-free survival and overall survival.

Multiple tumor-associated antigens have been defined, from which a number of vaccines have been developed and tested. “Most have approached the vaccine as a single agent rather than as a combination agent, either in a specific antigen, either synthetic, naked DNA, RNA, bacterial, or viral; whole-cell lysate, or anti-idiotype vaccine, and it is either given by itself or given in the context of a dendritic cell,” said Khleif, director of the Georgia Health Sciences Cancer Center in Augusta. Unfortunately, vaccines have demonstrated limited efficacy in this setting.

Ovarian cancer is an immune-driven tumor, but because of the immune-suppressive environment within it, T cells are activated and captured by various mechanisms, leading to an inability of the T cells to generate a proper immune response. These mechanisms include accumulation of intratumoral T regulatory cells (Tregs) that block an immune response, production of the enzyme IDO (leading to activation of suppressive populations of Tregs) by tumor cells, and suppression of effector T cells by engagement of PD-1 with PD-L1.

“When we think of our approach to vaccines, it’s pretty naïve to think that a vaccine is going to generate T cells, and the T cells are going to be taking care of a tumor that is that immune suppressive,” said Khleif.

Accordingly, the use of PD-1 inhibitors and other checkpoint inhibitors in ovarian cancer has been proposed, but so far, the data are scant. The expression of PD-1 in ovarian tumors is dependent on the grade of the tumor, with high-grade tumors having higher expression.

Hamanishi et al studied the activity of nivolumab (Opdivo) at 2 dosages (1 or 3 mg/kg every 2 weeks) in 20 patients with platinum-resistant ovarian cancer, producing 2 complete responses and 1 partial response.2 Levels of PD-L1 expression did not seem to influence response, “which might be a little bit different than other diseases like lung cancer,” he said.

A phase Ib study of avelumab (Bavencio), 10 mg/kg, in 124 patients demonstrated an objective response rate of 9.7% and stable disease in 44%.3 Another study of nivolumab in 17 patients with recurrent/refractory epithelial ovarian cancer, showed 1 partial response and 2 patients with stable disease after treatment. “As a single agent, so far, we have some responses but we did not break that tolerance yet,” Khleif said, and noted that the responses rarely lasted very long.

Multiplication of effort is probably needed to address the immune suppressive state of the tumor microenvironment in ovarian cancer, he said. “That is why combination immune therapy is going to be, and is, the name of the game.” Chemotherapy is known to induce PD-L1 expression and lead to enhanced infiltration of CD8-positive cells in the tumor, possibly enhancing the efficacy of checkpoint inhibitors.

Khleif’s team has found that Tregs and T conventional cells (Tconvs) are differentially regulated by PI3K isoforms. Tregs are primarily dependent on the PI3K-delta isoform, whereas in Tconvs, PI3K-alpha and -beta provide a redundant pathway to PI3K-delta. This dichotomy can be exploited to target Tregs by inhibiting the PI3K-delta isoform while leaving Tconvs intact.

In a mouse model of lung cancer, co-administration of an inhibitor of PI3K-delta with a tumor-specific vaccine decreased the number of suppressive Tregs and increased the number of vaccine-induced CD8 T cells within the tumor microenvironment, resulting in a large reduction in tumor volume. The results “offer a mechanistic rationale to employ PI3K-delta inhibitors to selectively target Tregs and improve cancer immunotherapy,” the authors concluded.

PARP is an important target in ovarian cancer. PARP inhibitors have been shown to have clear beneficial effects on clinical outcomes in the treatment of ovarian cancer in several clinical trials. The combination of a PARP inhibitor with CTLA-4 blockade improved overall survival in a BRCA1-deficient murine ovarian cancer model compared with treatment with CTLA-4 or PD-1/PD-L1 monoclonal antibodies alone.

A PARP inhibitor enhanced apoptosis and tumor volume shrinkage within the tumor microenvironment when given in addition to a PD-1/PD-L1 blocker. PARP inhibition was able to attenuate anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 re-sensitized the PARP inhibitor-treated cancer cells to T-cell killing, the authors found. Multiple trials combining PARP inhibitors and checkpoint inhibitors are ongoing, said Khleif.

Women who carry the BRCA1 or BRCA2 gene mutations now have the clearest picture yet of their risk of developing breast and ovarian cancer.

An Australian study led by the University of Melbourne, Peter MacCallum Cancer Centre and Cancer Council Victoria tracked almost 10,000 women with these mutations for up to 20 years.

What they found has given clinicians “enormous power” to assess a carrier’s risk of developing these cancers.

It will also provide carriers with greater confidence in the decisions they make about prevention strategies including surgery, says the oncologist Prof Kelly-Anne Phillips, founder of the Peter Mac Breast and Ovarian Cancer Risk Management Clinic.

“This is the largest and most scientifically rigorous study to date without question,” Phillips said. “We used data from a large number of studies running internationally in over 18 around the world.”

The study published in JAMA: The Journal of the American Medical Association found that women with BRCA1 mutations have on average a 72% risk of developing breast cancer by the age of 80.

For BRCA2 mutation carriers, the risk of breast cancer is 69%.

The average lifetime risk of ovarian cancer is 44% for BRCA1 and 17% for BRCA2.

It was also found that the location of where the abnormality is found in the gene and family history influenced the risk.

“So women who had these gene mutations who had more people in their family who’d been affected with breast and/or ovarian cancer had a higher likelihood of developing these cancers than women with the same mutation who had less of a family history,” Phillips said.

She said the findings also had significant implications for older women with these mutations. The study found cancer risk increased rapidly at a young age and peaked in the 30s for BRCA 1 mutation carriers and in the 40s for BRCA 2 mutation carriers.

But it remained as the woman aged, overturning previous thinking that the risk reduced when a woman turned 60 without a diagnosis.

“Our study really showed that the risk reaches its highest level in a woman’s 30s and remains well into their 80s,” Phillips said.

Further analysis of the data will examine whether modifiable lifestyle-related factors such as timing of pregnancies, contraceptive use or alcohol and smoking can influence the risk of cancer for these women.

Women with advanced ovarian cancer who expressed the tumor antigen NY-ESO-1 demonstrated shorter PFS and OS than those without the antigen, according to study results published in Gynecologic Oncology.

However, patients with NY-ESO-1–expressing tumors who enrolled in immunotherapy trials had significantly improved OS, researchers reported.

“The most significant finding of the present study is we have identified a biomarker for aggressive ovarian cancer that is not only highly expressed, but is targetable with immunotherapy,” Kunle Odunsi, MD, PhD, FRCOG,deputy director and chair of the department of gynecologic oncology at Roswell Park, told HemOnc Today.

Ovarian cancer is the most lethal gynecological malignancy in the United States, accounting for about 14,000 deaths in 2016, and only incremental improvements have been made in survival rates. In their study, Odunsi and colleagues at Roswell Park aimed to provide an update on the prevalence of NY-ESO-1 expression in ovarian cancer, assess the association between NY-ESO-1 expression and clinical outcomes, and evaluate the survival impact of targeting NY-ESO-1 with immunotherapy.

“NY-ESO-1 appears play a role in ovarian cancer similar to HER-2/neu in breast cancer, where overexpression is associated with a worse prognosis, until trastuzumab (Herceptin, Genentech) became available, and now those patients have improved outcomes,” Odunsi said. “Therefore, we encourage ovarian cancer patients to have their tumors tested for NY-ESO-1.”

Researchers offered 11 immunotherapy vaccine trials to the 408 women who tested positive for NY-ESO-1; 68 patients accepted. Women who enrolled tended to be younger (54.5 years vs. 64 years; P = .002) and had similar stage, grade and histology of disease.

Women who received immunotherapy had longer OS (75.3 months) than women who did not enroll (38 months; P < .001) and women without NY-ESO-1 expression (50 months; P = .046).

“The patients received various forms of NY-ESO-1–targeted vaccine therapies,” J. Brian Szender, MD, MPH, fellow in the department of gynecologic oncology at Roswell Park Cancer Institute, told HemOnc Today. “Our vaccine therapy approaches are focused on ovarian cancer patients in remission or with minimal residual disease burden in order to minimize the risk for relapse. For patients with large-volume disease, we have developed adoptive T-cell therapies using engineered T cells that are programed to bear T-cell receptors that recognize NY-ESO-1 in tumors.”

Researchers encourage patients with NY-ESO-1 expression to participate in vaccine clinical trials to reduce their risk for relapse.

“For patients with recurrent or progressive ovarian cancer who have failed more than two lines of standard chemotherapies, we encourage participation in clinical trials of adoptive T-cell therapy targeting NY-ESO-1,” Odunsi said. “Because NY-ESO-1 is not expressed by all patients, we have developed a clinical trial where NY-ESO-1 expression is enforced pharmacologically, followed by adoptive T-cell therapy with TCR–engineered cells targeting NY-ESO-1.”

A new study that followed 10,000 women provides more accurate, age-related estimates of the risk of developing breast and ovarian cancer in carriers of mutations of the BRCA1 and BRCA2 genes. It also suggests that family history and the location of the mutations on the gene should be taken into account.

The study – led by the University of Cambridge in the United Kingdom – is reported in JAMA.

The findings should help doctors to improve the advice and counseling they give on treatment options and risk-reducing lifestyle changes, suggest the researchers.

Lead author Antonis Antoniou, Ph.D., of Cambridge’s Department of Public Health and Primary Care, says, “We have been able to provide the most precise estimates of age-specific risks to date. These should provide more confidence in the counseling and clinical management of women with faults in the BRCA1 and BRCA2 genes.”

Cancer develops because of changes to genes that regulate the way that cells work, grow, and divide, causing them to get out of control.

Some of the genetic changes that lead to cancer are inherited, while others can arise during a person’s lifetime, due to either copy errors or environmental factors – such as exposure to tobacco smoke and radiation – that damage DNA.

Higher Risks From BRCA1 and BRCA2

Often, it is an accumulation of hundreds of genetic changes – each of which raises a person’s risk by a small amount – that causes cancer.

However, there are some genes, such as BRCA1 and BRCA2, where we know that mutations or errors in their code can greatly increase the risk of breast and ovarian cancer.

Normally, BRCA1 and BRCA2 help to protect against cancer, but certain mutations in one or both of the genes make cells “more likely to divide and change” more rapidly, giving rise to cancer.

The reason that the new study is significant is that until now, all risk assessments for patients with BRCA1 and BRCA2 mutations have relied on the results of “retrospective” studies – that is, those that look back on groups of patients who already have the disease.

Being “after the fact,” retrospective studies are prone to inherent problems such as bias and inaccuracies in recording and reporting of the desired information.

The new study is a prospective cohort study – it recruited a large group of nearly 10,000 cancer-free women with risk versions of BRCA1 and BRCA2 and followed them over a period, during which some of the women developed breast and ovarian cancer, while some did not.

Previous prospective studies of BRCA1 and BRCA2 have been done, but they have been very small – for example, the largest one had just 64 cases of breast cancer.

Age-Related Risk Profiles

When they analyzed the results, Dr. Antoniou and colleagues found that for carriers of BRCA1 mutations, the rates of breast cancer rose rapidly until the age of 30 to 40 years and then remained at the same level until the age of 80.

In the case of BRCA2 mutation carriers, the rates of breast cancer rose rapidly until the age of 40 to 50 years, and then also stayed at the same level until the age of 80.

The team found that the risk of developing breast cancer before the age of 80 was 72 percent for women carrying a faulty BRCA1 gene, and 69 percent for women carrying a faulty BRCA2 gene.

Similarly, the researchers found that the risk of developing ovarian cancer before the age of 80 was 44 percent for women carrying a faulty BRCA1 gene, and 17 percent for women carrying a faulty BRCA2 gene.

The risk of contralateral breast cancer – or developing cancer in the opposite breast – 20 years after having it diagnosed in the first breast was found to be 40 percent for carriers of a faulty BRCA1 gene, and 26 percent for carriers of a faulty BRCA2 gene.

However, in both breast and ovarian cancer, having a family history such as a relative diagnosed with one of the cancers would raise the risk. The amount of increase went up with the number of first- and second-degree relatives diagnosed with breast cancer.

Finally, the researchers discovered that the degree of cancer risk varies by position of the mutation within the BRCA1 or BRCA2 gene.

Dr. Charles Shapiro, director of Cancer Survivorship and Director of Translational Breast Cancer and Research at the Tisch Cancer Institute at Mount Sinai in New York City, NY, comments on the value of the new study:

“A single-institution [study] has too few of these women with inherited germ-line mutations to have sufficient numbers for valid statistical analysis. However, this study pooled the several results of several institutions leading to a relatively large sample. This combined analysis means there is more confidence in the results.”

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